Demyelination is a feature of many neurologic disorders. Demyelinating conditions are manifested in loss of myelinxe2x80x94the multiple dense layers of lipids and protein which cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). In patients with demyelinating conditions, demyelination may be irreversible; it is usually accompanied or followed by axonal degeneration, and often by cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin itselfxe2x80x94whether due to aberrant immune responses, local injury, ischemia, metabolic disorders, toxic agents, or viral infections [1, 23].
Central demyelination (demyelination of the CNS) occurs in several conditions, often of uncertain etiology, that have come to be known as the primary demyelinating diseases. Of these, multiple sclerosis is the most prevalent. Other primary demyelinating diseases include adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar myelopathy, HTLV-associated myelopathy, Leber""s hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, and tropical spastic paraparesis. In addition, there are acute conditions in which demyelination can occur in the CNS, e.g., acute disseminated encephalomyelitis (ADEM) and acute viral encephalitis. Furthermore, acute transverse myelitis, a syndrome in which an acute spinal cord transection of unknown cause affects both gray and white matter in one or more adjacent thoracic segments, can also result in demyelination. Finally, there are animal models which mimic features of human demyelinating diseases [23]. Examples include experimental autoimmune neuritis (EAN), demyelination induced by Theiler""s virus, and experimental autoimmune encephalomyelitis (EAE)xe2x80x94an autoimmune disease which is experimentally induced in a variety of species and which resembles MS in its clinical and neuropathological aspects [15, 21].
Multiple sclerosis (MS) is the most prevalent demyelinating condition. In Europe and North America, an average of 40-100 people out of every 100,000 have MS. The disease affects approximately 250,000 people in the United States alone. MS is a chronic, devastating neurological disease that affects mostly young adults. The pathogenesis of MS is a complex process that leads to destruction of myelin and oligodendroglia, as well as axonal damage, in the brain and spinal cord [1, 16]. Histopathologically, MS is characterized by inflammation, plaques of demyelination infiltrating cells in the CNS tissue, loss of oligodendroglia, and focal axonal injury [1]. The disease is thought to result from aberrant immune responses to myelin, and possibly non-myelin, self-antigens [17, 18]. Clinically, MS may follow a relapsing-remitting, or it may take a chronically progressive course with increasing physical disability [15]. Typically, the symptoms of MS include lack of co-ordination, paresthesias, speech and visual disturbances, and weakness [23].
Current treatments for the various demyelinating conditions are often expensive, symptomatic, and only partially effective, and may cause undesirable secondary effects. Corticosteroids (oral prednisone at 60-100 mg/day, tapered over 2-3 weeks, or intravenous methylprednisolone at 500-1000 mg/day, for 3-5 days) represent the main form of therapy for MS. While these may shorten the symptomatic period during attacks, they may not affect eventual long-term disability. Long-term corticosteroid treatment is rarely justified, and can cause numerous medical complications, including osteoporosis, ulcers, and diabetes [23].
Immunomodulatory therapy with recombinant human interferon-xcex2 (Betaseron and Avonex) and with co-polymer (Copaxon) slightly reduces the frequency of relapses in MS, and may help delay eventual disability [23]. Both forms of interferon-xcex2 and co-polymer are currently used as treatment modalities for MS, but all are exceedingly expensive. Immunosuppressive drugs (azathioprine, cladribine, cyclophosphamide, and methotrexate) are used for more severe progressive forms. However, they are not uniformly beneficial, and have significant toxic side-effects. Several drugs (e.g., baclofen at 30-60 mg/day in divided doses) may reduce spasticity by inhibiting the spinal cord reflexes. Cautious and judicious use is required, though, because the drug-induced reduction in spasticity in MS patients often exacerbates weakness, thereby further incapacitating the patient [23].
Similarly, current treatment for ALD, another devastating demyelinating disease, is relatively ineffective. Symptoms of ALD may include cortical blindness, corticospinal tract dysfunction, mental deterioration, and spasticity. Therapy to control the course of ALD may include bone marrow transplantation and dietary treatment [19], but inexorable neurological deterioration invariably occurs, ultimately leading to death [20, 23]. Some progress has been realized in the treatment of animals with EAE and EAN, by using glial cell transplants and growth factors, and by inhibiting adhesion molecules, autoantibodies, and cytokines [21]. However, none of these treatments has been shown to be beneficial in humans, and some require extensive neurosurgical intervention. Thus, it is clear from the foregoing that there exists a need for more effective, and less expensive and invasive, methods to treat the varied array of demyelinating conditions, without producing undesirable secondary effects.
Calcium-channel blockers are a class of pharmacological agents which inhibit the transmembrane flux of calcium (Ca2+) ions into cells, particularly vascular smooth muscle cells and cardiac muscle cells. They have been indicated for the treatment of angina, arrhythmias, atrial fibrillation, hypertension, and paroxysmal supraventricular tachycardia [14]. Amlodipine, a potent Ca2+-channel blocker, is a long-acting dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker). Amlodipine selectively inhibits Ca2+-ion influx across cell membranes, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. In particular, amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and a reduction in blood pressure. Amlodipine has been demonstrated to be effective in treating chronic stable angina, vasospastic angina, and hypertension [14], and it may also have neuroprotective activity [12]. Other Ca2+-channel blockers include bepridil, diltiazem, felodipine, flunarizine, isradipine, mibefradil, nicardipine, nifedipine, nimodipine, nisoldipine, nivaldipine, and verapamil [14].
The present invention is predicated on the discovery that a Ca2+-channel blocker, amlodipine, can ameliorate the clinical impairment of a demyelinating condition, EAE, which is commonly used as a model of MS. On the basis of this finding, the present invention provides a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject an amount of a Ca2+-channel blocker effective to treat the demyelinating condition.
The present invention is also directed to a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject a Ca2+-channel blocker in combination with a glutamate inhibitor, in amounts effective to treat the demyelinating condition. Also provided is a pharmaceutical composition comprising a Ca2+-channel blocker, a glutamate inhibitor, and a pharmaceutically-acceptable carrier.
Additionally, the present invention provides a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject a Ca2+-channel blocker in combination with a hypertensive agent, in amounts effective to treat the demyelinating condition. The present invention also discloses a pharmaceutical composition comprising a Ca2+-channel blocker, a hypertensive agent, and a pharmaceutically-acceptable carrier.